Novel optically active halo-substituted tetrahydrofurans

ABSTRACT

A process for producing the optically pure (+)- or (-) isomer of a pheynl- or substituted- phenylalkanolamine compounds having pharmacologic activity without the need for resolution processes and novel intermediates useful in the process including optically pure haloalcohols are provided.

This is a division of application Ser. No. 175,178 filed Mar. 30, 1988.

BACKGROUND OF THE INVENTION

A. Field of Invention

The present invention relates to an improved process for producingphenyl- or substituted-phenylalkanolamine compounds having pharmacologicactivity and to novel intermediates useful in the process, and moreparticularly relates to a process for directly obtaining the desired(+)- or (-) enantiomer in essentially 100% ee (enantiomeric excess)without the need for tedious resolutions.

Many biologically active compounds and medicinals are synthesized asracemic mixtures However, commonly, only one of the optical isomers hasthe desired properties, while the other may possess only very weak or adifferent, undesired pharmacological activity, or at worst, is toxic.This problem is best illustrated by the problems associated withThalidomide which was unfortunately marketed as a racemic mixture of thetoxic isomer, responsible for the well-publicized birth defects, as wellas the active optical isomer which was free from the teratological sideeffects. The Thalidomide tragedy could have been avoided had there beena simple, economical process available for separating the isomers. Sincethen, the pharmaceutical industry has employed tedious and expensiveresolution processes to insure that only the desired optical isomer ispresent in the finished formulation. It is therefore highly desirablefor the pharmceutical industry to be able to obtain one enantiomer in asimple, direct, less costly process.

Many pharmaceutically active compounds are phenyl-orsubstituted-phenylalkanolamines having the basic structure ##STR1##wherein n is 1 or 2, R¹ is hydrogen, acetoxy, phenyl or substitutedphenyl and R² is lower alkyl, phenyl or substituted phenyl.

Typical drugs of this kind include Isoproternol, Colterol,phenylephrine, Bitolerol, Dipeverfrin, and the major new anti-depressentagents, Tomoxetine, Fluoxetine and Nisoxetine.

Tomoxetine, [[R]-(-)-N-methyl- -(2-methylphenoxy)-benzenepropaminehydrochloride, Eli Lilly, and Company, LY 139603] is a new drugcurrently undergoing investigation as an antidepressant (R. L. Zerbe etal., J. Pharmacol. Exp. Ther. 1985, 232, 139). The (-)-optical isomerhas been shown to be nine times more potent than the (+)-isomer. Unlikechemical tricyclic antidepressants such as imipramine, (-)-Tomoxetinehas been shown to inhibit specifically norepinephrine uptake in humansat dosages which are clinically well tolerated and to be a relativelyweak ligand for α-1, α-2 and β-adrenergic receptors. The latterreceptors are generally regarded as responsible for undersirableside-effects associated with antidepressants.

The patent literature preparation of (-)-Tomoxetine involves a long andtedious procedure culminating in a highly inefficient resolution (20%)of the racemic mixture. See Molly et al. U.S. Pat. No. 4,018,895 andFoster et al. Eur. Patent No. 0052492. Clearly, an enantiomericpreparation of (-)-Tomoxetine is needed. The best procedure to dateprovides an overall yield of the (-)-isomer of 14% and an optical purityof only 88% ee. The present invention provides a simple synthesis ofboth (-)-Tomoxetine, (+)-Tomoxetine in essentially 100% ee, as well asboth optically pure enantiomers of the cognant compounds, Fluoxetine andNisoxetine.

In general, many of these valuable drugs in addition to the Lillyantidepressants discussed above are synthesized via the Mannich reactionto produce the amino substituted arylalkyl ketone. Reduction of theketone gives the alcohol. The mixture of enantiomeric arylalkanolaminesare then resolved in a generally tedious, costly inefficient process.

Thus, there exists a need for a more efficient, cost effective, simpleprocess for directly obtaining the desired isomer of Tomoxetine andother arylalkanolamine pharmaceutical agents in essentially 100%enantiomeric excess. The present invention provides such a process aswell as valuable intermediates useful in such process.

B. Prior Art

Recently, it was discovered that diisopinocamphylchloroborane, hereafterIpc₂ BCl, derived from either (+)- or (-)-alpha-pinene is capable ofreducing arylalkyl ketones to the corresponding alcohols in a highlyenantioselective fashion. (Brown et al., J. Org. Chem. 1985, 50, 5446.See also Herbert C. Brown copending U.S. patent application Ser. No.902,175 filed Aug. 29, 1986). The alcohols so obtained were simplecompounds, containing no other functionality, and as such wereend-products in themselves. However, for the construction of morecomplex molecules, often required of biologically active compounds,additional functionalities that can be further transformed aredesirable. The halides are a particularly appealing functional group.

Chiral haloalcohols have been prepared in variable enantiomeric excesswith a reagent developed by Itsuno et al. (J. Chem. Soc. Perkin Trans.I. 1985, 2615). In addition to inconsistant optical yields, the natureof the reagent remains in doubt. Soai et al. (J. Chem. Soc. Chem. Comm.1986, 1018) have demonstrated that a chirally modified lithiumborohydride can reduce beta-halogenoketones in 81-87% ee. Moreconsistent results have been obtained for asymmetric reduction of2-haloacetophenones with neat Alpine-Borane (Brown et al, J. Org. Chem.1985, 50, 1384).

In my copending application Ser. No. 902,175, filed Aug. 29, 1986, Idisclosed that diisopinocampheylhaloboranes (Ipc₂ BX) are exceptionallyeffective asymmetric reducing agents for simple phenylketones to thecorresponding alcohol. The reagents Ipc₂ BX appear to be the mosteffective currently available for such asymmetric reductions, and onewould expect that reduction of the arylalylketoamines should provide adirect route to the desired optically pure arylalkylaminoalcohols.Unfortunately, the presence of the amino groups prevents the desiredreaction. Tertiary amines coordinate with Ipc₂ BX to prevent its use forreduction. Primary and secondary amines react to give theamino-substituted boron compounds RNHBIpc₂ +HX.

The present invention provides a solution to that problem by providing amethod in which the Ipc₂ BX reagents are used to reduce ahalo-substituted arylalkylketone. Treatment of the haloaralkylalcoholwith the appropriate amine gives the desired optically purearylalkylaminoalcohol.

The present invention also fulfulls the need for a simple, reliablemethod of preparing each enantiomer of structurally diverse, opticallypure haloalcohols at will, which are intermediates in the preparation ofoptically pure phenoxyhalides which are useful as intermediates in thesynthesis of the optically pure, desired enantiomer of apharmaceutically active phenyl- or substituted-phenylalkanolamine.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an improved, simple,cost effective method of directly producing either optical isomer of apharmaceutically active arylalkanolamine represented by the formula##STR2## wherein R¹ is phenyl or substituted phenyl, n is an integerfrom 0 to 10 and R² and R³ each are hydrogen or lower alkyl, inessentially 100% ee without the need for resolution as well as noveloptically active intermediates useful in said process.

Generally speaking, the process of this invention, comprises the stepsof reducing a halo-substituted phenylalkylketone with optically pure(-)- or (+)-Ipc₂ BX to obtain the corresponding optically pure alcohol,and treating the alcohol with the appropriate amine to provide thedesired optically pure (+)- or (-)-arylalkylaminoalcohol.

The following reaction scheme summarizes the process of the preferredembodiments of this invention. ##STR3##

While in the preferred embodiment, the process of this invention isemployed in the synthesis of either optically pure isomer of Tomoxetinehydrochloride and related anti-depressants, Nisoxetine hydrochloride andFluoxetine hydrochloride, it can be used to synthesize essentially anyarylalkylaminoalcohol in optical purities of essentially 100% ee bysimply adjusting the starting materials and the amine employed in thereaction, as will be readily apparent to one skilled in the art.

In another embodiment, the present invention provides novel haloalcoholsof essentially 100% ee represented by the formula ##STR4## wherein eachR is the same or different member of the group consisting of fluoro,chloro, bromo or iodo.

As used herein, the term "essentially 100% ee" or "high state of opticalpurity" refers to an enantiomeric excess of >95%, as determined by anyanalytical technique, i.e. gas chromotography, proton magneticresonance, etc., on the derivatized or underivatized alcohols.

The term "lower alkyl", as used herein, refers to straight or branchedchain alkyl groups having from 1 to 8 carbon atoms, inclusive, i.e.,methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, n-pentyl,2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, n-octyl, 2-methylhexyl,2,3-dimethylheptyl, and the like.

The term "substituted phenyl", as used herein, refers to a phenyl grouprepresented by the forumula: ##STR5## wherein R1 and R² are the same ordifferent members of the group consisting of hydrogen, loweralkyl orhaloloweralkyl, with the limitation either R₁ or R₂ must be other thanhydrogen.

The term "lower alkoxy" refers to an alkoxy group having from 1-8 carbonatoms, such as methoxy, ethoxy, propoxy, etc.

The term "halo lower alkyl" refers to a lower alkyl group as definedabout containing from 1-4 halo substitutions, i.e., trifluoromethyl,1,3-dichlorobutyl and the like.

The present invention also provides a method for converting1,4-halohydrins of high optical purity to the correspondingtetrahydrofurans in which the optical purity of the alcohol is retainedin the cyclized products of the following general structure in which oneenantiomer is arbitrarily depicted. ##STR6## wherein R is halo (fluoro,chloro, bromo or iodo).

In addition, the present invention provides novel chiral1,3-phenoxychlorides following general formula in which one enantiomeris arbitrarily drawn. ##STR7## wherein R is lower alkyl, haloloweralkylor loweralkoxy. The 1,3-phenoxychlorides of this invention areintermediates in the preparation of the corresponding 1,3-phenoxyaminesor their salts with complete retention of optical activity. The1,3-phenoxyamines are represented by the formula ##STR8## wherein R¹ isphenoxy substituted with lower alkyl, haloloweralkyl or loweralkoxy, R²is hydrogen or lower alkyl and R³ is hydrogen or loweralkyl, or apharmaceutically acceptable salt thereof.

Representative 1,3-phenoxypropylamines include Tomoxetine, Nisoxetineand Fluoxetine.

In a preferred embodiment, the haloalcohols of this invention areprepared by reacting diisopinocampheylchloroborane, Ipc₂ BCl, with bothring and chain substituted haloaralkylketones to the correspondinghaloalchols in excellent enantiomeric exess (95% or better). In mostcases, simple recrystallization provides the pure enantiomers. Thechiral haloalcohols of the present invention are highly versatileintermediates. They can be readily cyclized to oxiranes and2-substituted tetrahydrofurans with retention of chirality. Using thismethodology, the present invention provides an efficient, highlyenantioselective synthesis of both optical isomers of the antidepreseentdrugs Tomoxetine, Fluoxetine and Nisoetine, from the antipodalintermediates, (+)- or (-)-3-chloro-1-phenyl-1-propanol.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples further illustrate the present invention. Unlessotherwise specified, all operations with organoboranes were performedunder nitrogen. Melting points and boiling points are uncorrected. ¹³ CNMR spectra were obtained on a Varian FT-80A spectrometer (20.00 MHz)relative to TMS. GC analysis was done on a Hewlett-Packard 58902 gaschromatograph-mass spectrometer Model 4000. Optical rotations wererecorded on a Rudolph Polarimeter Autopol III and were obtained at 23°C. unless otherwise specified. Reduction of ketones were carried out asdescribed in the literature, by Chandrasekharan, J.; Ramachandran, P. V.and Brown, H. C., J. Org. Chem. 1985 50, 5446 and Brown, H. C.;Chandrasekharan, J.; Ramachandran, P. V., J. Am. Chem. Soc. 1988 110,0000.

Tetrahydrofuran (Fisher), THF, was distilled from benzophenone ketyl andstored under nitrogen in an ampule. Diethyl ether (Mallincrodt), ethylacetate (Mallincrodt), dichloromethane (Mallincrodt), pentane(Phillips), and hexane (Fisher) were used as received. Anhydrousethereal hydrogen chloride was prepared from hydrochloric acid andsufuric acid using a Brown gasimeter. (Brown, H. C.; Kramer, G. W.;Levy, A. B.; Midland, M. M. "Organic Synthesis via Boranes", :WileyInterscience: New York, 1975). o-Cresol,-α, α, α-trifluoro-p-cresol,guaiacol, triphenylphosphine, diethylazodicarboxylate and aqueousmethylamine were purchased from the Alrdich Chemical Company. Reactionswere monitored where ever possible by TLC using Whatman precoated silicaplates. Neutral alumina (J. T. Baker & Company, Column Chromatography)was used for column chromatography.

The enantiomeric excess, ee, of the haloalcohols was determined byconversion to the MTPA esters, followed by analysis on a Methyl Siliconecolumn (50 m) or Supelcowax column (15 m). In all cases, racemicalcohols gave baseline separations and 1:1 ratios of integrated areas.

EXAMPLE 1 [S]-(-)-1-chloro-3-phenyl-3-propanol

A solution of 3-chloropropiophenone (8.93 50 mmol in 25 ml THF) wasadded to (-) diisopinocampheylchloroborane (Ipc₂ BCl, 18.0 g, 56 mmole,in 25 ml THF at -24° C.). The reaction was complete within 7 hours afterwhich all volatiles were removed under reduced pressure. The residue wasdissolved in ether, and diethanolamine (2 equivalents) was added. Theresulting suspension was stirred for two hours and filtered. The solidresidue was washed with ether and the combined washings and filtratewere concentrated. Distillation furnished[S]-(-)-1-chloro-3-phenyl-3-propanol. Yield: 6.1 g, 72%; mp 56°-57° C.;[α]_(D) ²³ -25.25, c=7.05, CHCl₃ ; 97% ee.

EXAMPLE 2 [R]-(+)-1-Chloro-3-phenyl-2-propanol

[R]-(+)-1-Chloro-3-phenyl-2-propanol was prepared by the method ofexample 1 except that (+)-diisopinocampheylchloroborane was used.[α]_(D) ²³ +25.3, c=7.05, CHCl₃ ; 97% ee.

EXAMPLES 3-28

The following novel optically active haloalcohols were preparedfollowing the methods of Examples 1 and 2 by reduction of theappropriate prochiral haloketone with (-)- or(+)-diisopinocampheylchloroborane:

    ______________________________________                                        Example    Compound                                                           ______________________________________                                        3          [S]-1-(2-bromophenyl)-1-ethanol                                    4          [R]-1-(2-bromophenyl)-1-ethanol                                    5          [S]-1-(4-bromophenyl)-1-ethanol                                    6          [R]-1-(4-bromophenyl)-1-ethanol                                    7          [S]-1-(4-chlorophenyl)-1-butanol                                   8          [R]-1-(4-chlorophenyl)-1-butanol                                   9          [S]-1-chloro-2-(2,4-dichlorophenyl)-2-                                        ethanol                                                            10         [R]-1-chloro-2-(2,4-dichlorophenyl)-2-                                        ethanol                                                            11         [S]-1-chloro-4-(4-bromophenyl)-4-butanol                           12         [R]-1-chloro-4-(4-bromophenyl)-4-butanol                           13         [S]-1-(3-fluorophenyl)-1-ethanol                                   14         [R]-1-(3-fluorophenyl)-1-ethanol                                   15         [S]-1-(4-fluorophenyl)-1-ethanol                                   16         [R]-1-(4-fluorophenyl)-1-ethanol                                   17         [S]-1-(2,4-difluorophenyl)-1-ethanol                               18         [R]-1-(2,4-difluorophenyl)-1-ethanol                               19         [S]-1-(2,5-difluorophenyl)-1-ethanol                               20         [R]-1-(2,5-difluorophenyl)-1-ethanol                               21         [S]-1-(2,6-difluorophenyl)-1-ethanol                               22         [R]-1-(2,6-difluorophenyl)-1-ethanol                               23         [S]-1-(3,4-difluorophenyl)-1-ethanol                               24         [R]-1-(3,4-difluorophenyl)-1-ethanol                               25         [S]-1-chloro-2-(4-fluorophenyl)-2-                                            ethanol                                                            26         [R]-1-chloro-2-(4-fluorophenyl)-2-                                            ethanol                                                            27         [S]-1-chloro-4-(4-fluorophenyl)-4-butanol                          28         [R]-1-chloro-4-(4-fluorophenyl)-4-butanol                          ______________________________________                                    

Table I summarizes the above representative novel optically activehaloalcohols of the present invention which are represented by FormulaI.

                  TABLE I                                                         ______________________________________                                         ##STR9##                      (I)                                            R.sub.2                                                                            R.sup.3                                                                              R.sup.4                                                                              R.sup.5                                                                            R.sup.6                                                                            R.sup.7                                                                            n    % ee  abs. config                      ______________________________________                                        Br   H      H      H    H    H    1    99    S                                Br   H      H      H    H    H    1    99    R                                H    H      Br     H    H    H    1    97    S                                H    H      Br     H    H    H    1    97    R                                H    H      H      H    H    Cl   3    98    S                                H    H      H      H    H    Cl   3    98    R                                Cl   H      Cl     H    H    Cl   1    95    S                                Cl   H      Cl     H    H    Cl   1    96    R                                H    H      Br     H    H    Cl   3    98    S                                H    H      Br     H    H    Cl   3    98    R                                H    F      H      H    H    H    1    96    S                                H    F      H      H    H    H    1    96    R                                H    H      F      H    H    H    1    97    S                                H    H      F      H    H    H    1    97    R                                F    H      F      H    H    H    1    96    S                                F    H      F      H    H    H    1    96    R                                F    H      H      F    H    H    1    96    S                                F    H      H      F    H    H    1    96    R                                F    H      H      H    F    H    1    96    S                                F    H      H      H    F    H    1    96    R                                H    F      F      H    H    H    1    95    S                                H    F      F      H    H    H    1    95    R                                H    H      F      H    H    Cl   3    98    S                                H    H      F      H    H    Cl   3    98    R                                ______________________________________                                    

In the above examples, the S isomer was obtained from (-)-Ipc₂ BCl andthe R isomer was obtained from (+)-Ipc₂ BCl. All reductions wereperformed in THF at approximately 2M. The % ee was determined as the(+)-MTPA ester.

EXAMPLES 29-46

Following the process of Example I, the following haloalcohols areprepared from the corresponding haloketone and either (-)- or(+)-diisopinocampheylchloroborane:

    ______________________________________                                        Example     Compound                                                          ______________________________________                                        29          [S]-(-)-1-iodo-3-phenyl-2-propanol                                30          [R]-(+)-1-iodo-3-phenyl-2-propanol                                31          [S]-1-(2-iodophenyl)-1-ethanol                                    32          [R]-1-(2-iodophenyl)-1-ethanol                                    33          [S]-1-(4-iodophenyl)-1-ethanol                                    34          [R]-1-(4-iodophenyl)-1-ethanol                                    35          [S]-1-(4-iodophenyl)-1-butanol                                    36          [R]-1-(4-iodophenyl)-1-butanol                                    37          [S]-1-iodo-2-(2,4-dichlorophenyl)-2-                                          ethanol                                                           38          [R]-1-iodo-2-(2,4-dichlorophenyl)-2-                                          ethanol                                                           39          [S]-1-iodo-4-(4-bromophenyl)-4-butanol                            40          [R]-1-iodo-4-(4-bromophenyl)-4-butanol                            41          [S]-1-(3-fluorophenyl)-1-pentanol                                 42          [R]-1-(3-fluorophenyl)-1-pentanol                                 43          [S]-1-(4-iodophenyl)-1-octanol                                    44          [R]-1-(4-fluorophenyl)-3-propanol                                 45          [S]-1-(2,4-difluorophenyl)-3-propanol                             46          [R]-1-(2,4-diiodo-1-hexanol)                                      ______________________________________                                    

The novel optically active tetrahydrofurans of the present invention arerepresented by Formula II ##STR10## wherein R is halo. The preparationof the optically active tetrahydrofurans of this invention areillustrated in Examples 47-50.

EXAMPLE 47 [S]-2-(4-bromophenyl)-tetrahydrofuran

A solution of [S]-1-chloro-4-(4-bromophenyl)-4-butanol (50 mmol) in THF(25 ml) was added to a cooled suspension (0° C.) of NaH (55 mmol) in THF(50 ml). After being stored for 2 h at 25C, the reaction mixture wasquenched with water, brought to pH 6 with concentrated HCl, andextracted with ether (2×50 ml). The organic phase was dried over H₂ SO₄,filtered and all volatiles removed under reduced pressure. The residuewas distilled to provide the product in 75% yield, 98% ee as determinedon a chiral capillary column of Ni(HFN-IR-Cam)₂.

EXAMPLES 48-50

The following representative optically active 2-substitutedtetrahydrofurans were prepared by the method of Example 47 from thecorresponding optically active haloalcohol.

    ______________________________________                                        Example  Compound                % ee                                         ______________________________________                                        48       [S]-2-(4-fluorophenyl)-tetrahydrofuran                                                                98                                           49       [R]-2-(4-fluorophenyl)-tetrahydrofuran                                                                98                                           50       [R]-2-(4-bromophenyl)-tetrahydrofuran                                                                 98                                           ______________________________________                                    

EXAMPLES 51-54

The following representative are also prepared following the method ofExample 47: [S]-2-(4-iodophenyl)-tetrahydrofuran;[R]-2-(4-iodophenyl)-tetrahydrofuran;[S]-2-(4-chlorophenyl)-tetrahydrofuran; and[R]-2-(4-chlorophenyl)-tetrahydrofuran.

The 1,3-halohydrins of Formula I are converted to novel1,3-phenoxyhalides represented by Formula III below which are importantintermediates in the preparation of biologically active propylamines.The novel optically active 1,3-phenoxychlorides of the present inventionare presented by the formula: ##STR11## wherein R is phenoxy substitutedby lower alkyl, loweralkoxy or haloloweralkyl. The preparation ofrepresentative 1,3-phenoxychlorides is described in the followingexamples.

EXAMPLE 55 [R]-(-)-1-Chloro-3-phenyl-3-(2-methylphenoxy)propane

Triphenylphosphine (5.25 g, 20 mmol) and ethylazodicarboxylate (3.15 ml,3.48 g, 20 mmol) were added to a solution of[S]-1-chloro-3-phenyl-3-propanol (3.4g, 20 mmol) and cresol (2.06 ml,2.16 mmol) in THF (50 ml). The mixture was stirred at room temperatureovernight until the reaction was complete as determined by TLC. THF wasremoved under aspirator vacuum and the residue treated with pentane(3×50 ml). The combined pentane fractions were concentrated and theresidue chromatographed on neutral alumina. Elution with pentane andremoval of solvent afforded 3.6 g (70% yield) of the chloro ether as athick liquid which was found to be 99% pure by gas chromatograph. Bp180°-200° C./0.5 mm; [α]_(D) ²³ -21.7° (c 3.9, CHCl₃); ¹³ C-NMR :150.67,147.81, 128,76, 127,98, 125.32, 122.23, 120.96, 117.35, 112.71, 59.02,56.02, 41.61. Mass spectrum (EI): 260/262 (1,M⁺ ), 224 (1, M⁺ -HCl), 153(21, M⁺ -C₇ H₈ O), 91 (100, C₇ H₇). (CI): 261 (7.4, M⁺ +H), 153/155(100, M⁺ +H-C₇ H₈).

EXAMPLE 56 [R]-(-)-Tomoxetine Hydrochloride

To the chloroether of Example 55 (2.6 g, 10 mmol) in a Paar"mini-reactor" was added aqueous methylamine (40%, 20 ml). Ethanol (10ml) was added as a cosolvent and the solution heated at 30° C. for 3hours. The solution was cooled to room temperature and the mixture waspoured on water (150 ml) and extracted with ether. The ether extract waswashed with water, brine and dried over MgSO₄. HCl in EE (5 ml of 3.2 M,16 mmol) was added to the decanted solution.

EXAMPLE 57 [S]-(+)-1-Chloro-3-phenyl-3-(2-methylphenoxy)propane

This chloroether was prepared following the method of Example 55, using[R]-3-chloro-1-phenylpropanol (3.4 g, 20 mmol), o-cresol (2.06 ml, 20mmol), triphenylphosphine (5.25 g, 20 mmol) and diethylazodicarboxylate(3.15 ml, 20 mmol) in THF (50 ml). Workup yielded the title compound(3.5 g, 68%) as a thick liquid, bp 180°-200° C./0.5 mm; [α]_(D) ⁺²¹.7 (c3.9, CHCl₃); ¹³ C NMR and the mass spectra were identical to the[R]-(-)-isomer of Example 55.

EXAMPLE 58 [S]-(+)-Tomoxetine Hydrochloride

[S]-Tomoxetine hydrochloride was prepared using the same procedure asfor the preparation of the [R]-(-)-isomer from the chloroether ofExample 57 and excess aqueous methylamine in a "minireactor" at 130° C.for 3 hours. Workup provided the optically pure [S]-(+)-isomer in 95%yield, [α]_(D) ²³ +42.9° (c 6, MeOH). All spectral data are identical to[R]-(-)-Tomoxetine hydrochloride. Anal. Calcd. for C₁₇ H₂₂ ClNO: C,69.98; H, 7.55; Cl, 12.18; N, 4.9. Found: C, 69.1; H, 7.9; Cl, 12.29; N,4.91.

EXAMPLE 59 [R]-(+)-1-chloro-3-phenyl-3-(4-trifluoromethylphenoxy)propane

The title compound was prepared by the method of example 55 using[S]-3-chloro-1-phenylpropanol (2.57g, 15 mmol), α,α,α-trifluorocresol(2.4 g, 15 mmol) in THF (40 ml) at room temperature. Workup provided theoptically pure title compound as a thick liquid, bp 180°-200° C./0/5 mm.[α]_(D) +2.3° (c 10, CHCl₃ ; ¹³ C NMR (CDCl₃): 140.50, 129.39, 128.66,127,56, 127.38, 127.19, 127.01, 126.34, 116.45, 77.82, 41.69, 41.38.Mass spectrum (El): 153/155 (45), 91 (100). (CI): 314/316, (1, M⁺),153/155 (100). Anal. Calcd. for C₁₆ H₁₄ ClNO: C, 61.05; H, 4.45; Cl,11.29; F, 18.12. Found: C, 61.06; H, 4.51; Cl, 11.16; F, 18.22.

EXAMPLE 60 [R]-(-)-Fluoxetine Hydrochloride

[R]-(-)-Fluoxetine hydrochloride was prepared following the procedure ofExample 56 for [R]-(-)-Tomoxetine hydrochloride utilizing[R]-(+)-1-chloro-3-phenyl-3-(trifluoromethylphenoxy)propane (Example 59)(1.57 g, 5 mmol) and excess aqueous methylamine in ethanol as cosolventin a "minireactor" at 130° C. for 3 hours. Workup provided 1.55 g, 90%yield, of the recystallized, optically pure (CH₂ Cl₂ /EtOAc)[R]-(-)-Fluoxetine hydrochloride: mp 142°-143° C.; [α]_(D) ²² +3.01° (c5.3, MeOH); [α]_(D) ²² -15.52° (c 7.15, CHlC₃); ¹³ C NMR (CDCl₃) 160.10,139.46, 129.28, 128.66, 127.35, 127.16, 126.96, 126.77, 126.08, 116.26,55.49, 46.32, 34.77, 33.13. Mass spectrum (EI): 44 (100, CH₂ NHMe).(CI): 310 (100, M⁺ +H), 148 (12). Anal. calcd. for C₁₇ H₁₉ ClF₃ NO: C,59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 59.02; H, 5.6;N, 4.13; F, 16.67; Cl, 10.5.

EXAMPLE 61 [S]-(-)-1-chloro-3-phenyl-3-(4-trifluoromethylphenoxy)propane

The title chloro ether was prepared from[R]-(+)-3-chloro-1-phenylpropanol (2.56g, 15 mmol),α,α,α-trifluoro-p-cresol (2.43g, 15 mmol), triphenylphospine (3.93g, 15mmol) and diethylazodicarboxylate (2.36 ml, 15 mmol) in THF (40 ml) atroom temperature. Workup provided the title compound as a thick liquid.Yield: 3.07 g, 65%, bp 180°-200° C./0.5 mm [α]_(D) -2.2° (c 12.5,CHCl₃): ¹³ C NMR and mass spectrum were identical to those of the[R]-(-) isomer of Example 59.

EXAMPLE 62 [S]-(+)-Fluoxetine Hydrochloride

[S]-(+)-Fluoxetine hydrochloride was prepared following the method ofExample 60 from the chloro ether of Example 61 (1.59 g, 5 mmol) andexcess aqueous methylamine in ethanol as cosolvent in a "mini-reactor"at 130° C. for 3 hours. Workup provided 1.55 g (95%) of therecystallized (CH₂ Cl₂ /EtOAc) optically pure title compound, mp142°-143° C.: [α]_(D) ²² -3.04° (c 5.9, MeOH), [α]_(D) ²² +15.83° (cCHCl₃); ¹³ C NMR (CDCl₃): 160.08, 139.44, 129.26, 128.64, 127.30,127.12, 126.76, 116.25, 77.48, 46.32, 34.77, 33.14. Mass spectrum (EI):44 (100, CH₂ NHMe). (CI): 310 (100, M⁺ +H), 148 (12). Anal. calcd. forC₁₇ H₁₉ ClF₃ NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found:C, 58.70; H, 5.58; N, 4.29; F, 16.38; Cl, 10.35.

EXAMPLE 63 [R]-(+)-1-chloro-3-phenyl-3-2-methoxyphenoxy)propane

The title chloroether was prepared by the method of Example 55 using[S]-(-)-3-chloro-1-phenylpropanol (1.71 g, 10 mmol), guaiacol (1.1 ml,10 mmol), Ph₃ P (2.62 g, 10 mmol) and diethylazodicarboxylate (1.57 ml,10 mmol) in THF (40 ml) at room temperature. Workup and chromatographywith neutral alumina (hexane/ethyl acetate: 97.3) gave 1.7 g (62%) ofthe title compound as a thick liquid, bp 180°-200° C./0.5 mm. Theliquid, upon cooling, solidified and was recrystallized from pentane, mp59°-61° C. [α]_(D) +40.96 (c 7.8, CHCl₃): ¹³ C NMR (CdCl₃): 150.67,147.81, 141.28, 128,76, 127.98, 126.32, 122.23, 120.96, 117.35, 112.71,79.02, 56.07, 41.61. Mass spectrum (EI): 276/278 (1, M⁺), 240 (M⁺ -HCl),260/262 (M-CH₄), 91 (100), 124 (82). (CI): 277/279 (13.6, M⁺ +H),153/155 (100). Anal. calcd. for C₁₇ H₂₂ ClNO₂ : C, 69.44; H, 6.15; Cl,12.84. Found: C, 69.67; H, 6.3; Cl, 12.65.

EXAMPLE 64 [R]-(+)-Nisoxetine hydrochloride

[R]-(+)-Nisoxetine hydrochloride was prepared from the chloroether ofExample 63 (1.35 g, 5 mmol) and excess aqueous methylamine in ethanol (1ml) in a "mini-reactor" at 130° C. for 3 hours. Workup gave 1.41 g((91%) of recrystallized product (Ch₂ Cl₂ /EtOAc), mp 149°-150° C.;[α]_(D) +51.88° (c 4.8, MeOH); ¹³ C NMR: 150, 140.18, 129.29, 129.07,128.58, 126.14, 123.03, 121.32, 117.29, 112.23, 81.83, 56.44, 47.56,34.20, 33.19. Mass spectrum (EI): 167, 44 (100), 148 (8). (CI): 272(100, M⁺). Anal. Calcd. for C₁₇ H₂₂ ClNO₂ : C, 66.34; H, 7.15; N, 4.55;Cl, 11.5. Found: C, 66.08; H, 5.2; N, 4.66; Cl, 11.59.

EXAMPLE 66 [S]-(-)-Chloro-3-phenyl-3-(2-methoxyphenoxy)propane

The title chloroether was prepared in a manner similar to Example 64.Yield: 1.64 g (60%). Mp 59°-61° C.; [α]_(D) -41.6 (c 3, CHCl₃); ¹³ C NMRand mass spectrum were identical to the chloroether of example 64.

EXAMPLE 67 [S]-(-)-Nisoxetine Hydrochloride

[S]-(-)-Nisoxetine hydrochloride was prepared from[S]-(-)-chloro-3-phenyl-3-(2-methoxyphenoxy)propane by the method ofExample 65 to yield 1.41 g (91%) of the optically pure product. Mp149°-151° C.; [α]_(D) -52° C. (c 5, MeOH). ¹³ C NMR and mass spectrawere idential to that of the [R]-(+)-isomer.

The conversion of optically active 1,3-phenoxychlorides to thecorresponding 1,3-phenoxyamines with complete retention of opticalactivity has been illustrated in the above representative examples. Theprocess of this invention is applicable as a general method for thepreparation of any (+) or (-) Tomoxetine, Fluoxetine or Nisoxetineanalog in 100% optical purity. Referring to the following generalformula for such derivatives: ##STR12## any substituent or substituentson the phenyl ring can be accomodated for reduction with Ipc₂ BCl. Anychain length is also compatible with the process of this invention.

The process of this invention is also broadly applicable to thepreparation of the desired, optically pure isomer of any aryalkanolaminepharmaceutical agent.

The invention claimed is:
 1. A novel, optically active tetrahydrofuranof essentially 100% ee represented by the formula ##STR13## wherein R ishalo selected from the group consisting of chloro, fluoro, bromo andiodo.
 2. A compound of claim 1, [S]-2-(4-bromophenyl)-tetrahydrofuran.3. A compound of claim 1, [R]-2-(4-bromophenyl)-tetrahydrofurna.
 4. Acompound of claim 1, [S]-2-(4-fluorophenyl)-tetrahydrofuran.
 5. Acompound of claim 1, [R]-2-(4-fluorophenyl)-tetrahydrofuran.
 6. Acompound of claim 1, [S]-2-(4-iodophenyl)-tetrahydrofuran.
 7. A compoundof claim 1, [R]-2-(4-iodophenyl)-tetrahydrofuran.
 8. A compound of claim1, [S]-2-(4-chlorophenyl)-tetrahydrofuran.
 9. A compound of claim 1,[R]-2-(4-chlorophenyl)-tetrahydrofuran.